The prostacyclin analogue carbacyclin inhibits Ca2+-activated K+ current in aortic baroreceptor neurones of rats
The prostacyclin analogue carbacyclin inhibits Ca2+-activated K+ current in aortic baroreceptor neurones of rats
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DOI：
10.1111/j.1469-7793.1997.275bn.x
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发表时间：
1997-06-01
影响因子：
5.5
通讯作者：
Abboud, FM
中科院分区：
文献类型：
--
作者：
Li, Z;Lee, HC;Abboud, FM
1.前列环素(PGI(2))可增强压力感受性传入纤维的活性。本研究的目的是验证前列腺素I(2)抑制培养的压力感受器神经元钙激活钾电流(I-K(CaO))的假说。将大鼠结状神经节内的压力感受器神经元分离前1~2周，用荧光染料(DII)标记主动脉弓内的压力感受器神经元。采用全细胞膜片钳技术记录保持电位为-40 mV的去极化电压阶跃诱发的压力感受器神经元外向钾电流。压力感受器神经元暴露于稳定的PGI(2)类似物卡他环素可显著抑制稳态K+电流，且呈剂量依赖性和可逆性。K+电流的抑制不是由细胞内钙离子浓度的变化间接引起的。钙激活的钾通道阻断剂查氏毒素(ChTX，10(-7)M)也抑制钾电流。在有ChTX或无Ca~(2+)存在的情况下，卡巴环素不能抑制残余KF电流。此外，在高浓度的卡巴环素存在下，ChTX不会引起K+电流的进一步降低。卡巴环素对I-K(Ca)的抑制作用可被8-溴-cAMP和GTP-γS激活G-蛋白所模拟。卡巴环素对I-K(Ca)的抑制作用可被阻断G-蛋白激活的国内生产总值β-S和cAMP依赖的蛋白激酶选择性抑制剂PKI_5-24.5所阻断。结果表明，卡巴环素通过G蛋白偶联激活cAMP依赖的蛋白激酶，抑制主动脉压力感受器神经元对ChTX敏感的I-K(Ca)。这一机制可能与PGI(2)引起的压力感受器活动增加有关。
1. Previous studies indicate that prostacyclin (PGI(2)) increases the activity of baroreceptor afferent fibres. The purpose of this study was to test the hypothesis that PGI(2) inhibits Ca2+-activated K+ current (I-K(CaO)) in isolated baroreceptor neurones in culture.2. Rat aortic baroreceptor neurones in the nodose ganglia were labelled in vivo by applying a fluorescent dye (DiI) to the aortic arch 1-2 weeks before dissociation of the neurones. Outward K+ currents in baroreceptor neurones evoked by depolarizing voltage steps from a holding potential of -40 mV were recorded using the whole-cell patch-clamp technique.3. Exposure of baroreceptor neurones to the stable PGI(2) analogue carbacyclin significantly inhibited the steady-state K+ current in a dose-dependent and reversible manner. The inhibition of K+ current was not caused indirectly by changes in cytosolic Ca2+ concentration. The Ca2+-activated K+ channel blocker charybdotoxin (ChTX, 10(-7) M) also inhibited the K+ current. In the presence of ChTX or in the absence of Ca2+, carbacyclin failed to inhibit the residual Kf current. Furthermore, in the presence of high concentrations of carbacyclin, ChTX did not cause further reduction of K+ current.4. Carbacyclin-induced inhibition of I-K(Ca) was mimicked by 8-bromo-cAMP and by activation of G-protein with GTP gamma S. The inhibitory effect of carbacyclin on I-K(Ca) was abolished by GDP beta S, which blocks G-protein activation, and by a selective inhibitor of cAMP-dependent protein kinase, PKI5-24.5. The results demonstrate that carbacyclin inhibits ChTX-sensitive I-K(Ca) in isolated aortic baroreceptor neurones by a G-protein-coupled activation of cAMP-dependent protein kinase. This mechanism may contribute to the PGI(2) induced increase in baroreceptor activity demonstrated previously.